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Combination therapy of Anti-her3 antibodies

a technology of anti-her3 antibodies and conjugates, which is applied in the field of conjugation therapy of anti-her3 antibodies, can solve the problems of poor patient prognosis, correlates or associations of overexpression of egfr, and achieve the effect of inhibiting the dimerization of her2

Inactive Publication Date: 2016-06-09
F HOFFMANN LA ROCHE INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a combination therapy using two antibodies that target different proteins in cancer cells. One of the antibodies is specifically targeted to HER3, while the other antibody targets HER1. Surprisingly, it was found that the combination therapy was more effective in inhibiting tumor growth compared to either antibody alone, even in tumors where the other antibody only showed limited effectiveness. This was achieved by glycosylating the antibodies with a specific sugar chain that contains a high amount of fucose.

Problems solved by technology

In many of these conditions, the overexpression of EGFR correlates or is associated with poor prognosis of the patients.

Method used

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  • Combination therapy of Anti-her3 antibodies
  • Combination therapy of Anti-her3 antibodies
  • Combination therapy of Anti-her3 antibodies

Examples

Experimental program
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Effect test

example 1

Immunisation

[0216]NMRI mice were immunized with hHER3-ECD (inhouse) and boosted with hu-HER3-ECD. The immune response was monitored by testing serum samples against the HER1 / 2 / 3-ECD-ELISA. Spleen cells from mice with sufficient titers of anti-HER3 immunoglobulin were frozen for later immortalization by fusion with mouse myeloma cell line P3X63 Ag8.653. One fusion was done and hybridoma supernatants screened by HER1 / 2 / -ECD-ELISA showing no cross-reacivity, but binding to HER3-ECD and anti-HER3 selective hybridomas were selected. The relevant hybridomas were cloned by single cell FACS sorting. Single cell clones from different hybridomas were cultured in vitro to produce antibody in tissue culture medium for characterization. Antibodies were selected by determining their ability to inhibit HER3 phosphorylation, AKT phosphorylation and tumor cell proliferation of MDA-MB-175 cells (see Examples below). From the obtained antibodies, one was further humanized to give the following antibod...

example 2

Binding Assays

[0218]a) Antigene Specific ELISA for Binding to Human HER3 ECD

[0219]Soluble human HER3 extracellular domain fused to Streptavidin Binding Protein (SBP) was captured on a sreptavidine plate. To define optimal binding of the antibody to SPB-CDCP1, 384-well polystyrene plates (NUNC, streptavidin-coated) delivered by MicroCoat, Bernried, Germany (ID-No. 1734776-001) have been coated with pure and stepwise diluted HEK293 supernatant (in BSA / IMDM buffer:100 mg / ml BSA Fraction V, Roche 10735078001, dissolved in Iscove's Modified Dulbeccos Medium). Using mouse a calibration curve of chimeric 205 antibodies the optimal dilution factor of the HEK293 supernatant in relation to the streptavidin binding capazity of the microtiter plate was identified. For the standard coating, SBP-HER3 containing HEK293 supernatant was diluted (between 1:15 and 1:40) and incubated overnight at 2-80 C (25 μl per well). Intensive washing of the microtiter plate is necessary to remove remaining unboun...

example 3

a) Inhibition of HER3 Phosphorylation in MCF7, FaDu and Mel-Juso Cells

[0226]Assays were performed in MCF7 and FaDu cells according to the following protocol: Seed cells with 500,000 cells / well into Poly-D-Lysine coated 6-well plate in RPMI1640 medium with 10% FCS. Incubate for 24 h. Remove medium by aspirating, incubate overnight with 500 μl / well RPMI 1640 with 0.5% FCS. Add antibodies in 500 μl RPMI 1640 with 0.5% FCS. Incubate for 1 h. Add HRG-1b (final concentration 500 ng / ml) for 10 min. To lyse the cells remove medium and add 80 μl ice cold Triton-X-100 cell lysis buffer and incubate for 5 minutes on ice. After transferring the lysate into 1.5 ml reaction tube and centrifugation at 14000 rpm for 15 min at 4° C., transfer supernatant into fresh reaction tubes. Samples containing equal amounts of protein in SDS loading buffer were separated on SDS PAGE and blotted by using a semi-dry Western Blot to nitrocellulose membranes. Membrans were blocked by 1×NET-buffer+0.25% gelatine fo...

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PUM

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Abstract

The present invention relates to the combination therapy of anti-HER3 antibodies with certain anti-HER antibodies.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. application Ser. No. 14 / 151,626 filed on Jan. 9, 2014, now U.S. Pat. No. 9,180,185, which claims priority to European Patent Application No. EP 13151076.0 filed Jan. 11, 2013, the disclosures of both of which are incorporated herein by reference in their entirety.SEQUENCE LISTING[0002]The present application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Jan. 7, 2014, is named P5733US_ST25.txt and is 54,072 bytes in size.FIELD OF THE INVENTION[0003]The present invention relates to the combination therapy of anti-HER3 antibodies with certain anti-HER antibodies.BACKGROUND OF THE INVENTION[0004]Human HER3 (ErbB-3, ERBB3, c-erbB-3,c-erbB3, receptor tyrosine-protein kinase erbB-3, SEQ ID NO: 17) encodes a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosi...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K16/28C07K16/30C07K16/32
CPCC07K16/2863C07K16/32C07K16/3015C07K2317/24C07K2317/732C07K2317/565C07K2317/92A61K2039/507C07K2317/76A61K2039/505C07K2317/41C07K2317/73A61K39/3955A61P1/00A61P1/18A61P13/08A61P15/00A61P35/00A61P43/00
Inventor BAUSS, FRIEDERBOSSENMAIER, BIRGITFRIESS, THOMASGERDES, CHRISTIANHASMANN, MAXTHOMAS, MARLENEWEISSER, MARTIN
Owner F HOFFMANN LA ROCHE INC
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